Cohen-Gibson Syndrome

Cohen-Gibson syndrome is an overgrowth and intellectual disability syndrome caused by heterozygous variants in EED, a core component of the polycomb repressive complex 2. It resembles Weaver syndrome, which is caused by EZH2 variants.

Pathophysiology. EED stabilises polycomb repressive complex 2 and allows it to place the repressive H3K27me3 mark on chromatin. Pathogenic missense variants reduce this activity and derepress growth related genes.

Most variants are de novo.

Only a small number of patients have been described, so the full spectrum is still being defined.

• Prenatal or postnatal overgrowth: tall stature, macrocephaly
• Advanced bone age
• Intellectual disability from mild to severe, and speech delay
• Hypotonia and joint laxity
• Facial features: a broad forehead, hypertelorism, a flat nasal bridge, and a long philtrum
• Scoliosis and, in some, camptodactyly
• Umbilical hernia
• Behavioural issues, autism features and seizures in a minority
• Brain MRI: normal in most, with some ventricular enlargement

• EED sequencing with deletion and duplication analysis, within an overgrowth gene panel or exome sequencing.
• Parental testing to confirm de novo origin.
• Growth and bone age assessment, with radiography of the spine for scoliosis.
• Developmental assessment.
• Brain MRI if seizures or neurological signs.
• Echocardiography and abdominal ultrasound.

Differential diagnosis.

• Weaver syndrome (EZH2) and the SUZ12 overgrowth disorder
• Sotos syndrome (NSD1)
• Malan syndrome (NFIX)
• Tatton-Brown-Rahman syndrome (DNMT3A)
• Beckwith-Wiedemann spectrum
• Marfan syndrome

• Growth and endocrine care: monitor height, weight and head circumference, and assess pubertal timing. Treatment of tall stature is rarely needed.
• Scoliosis and joint laxity: yearly spine review, bracing for curves of 20 to 40 degrees, and surgery for progressive curves over 40 degrees.
• Hernia repair for symptomatic umbilical hernia.
• Development and education: early intervention, speech therapy, physiotherapy and special education.
• Behaviour: behavioural support, with sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily for anxiety.
• Epilepsy: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily.
• Tumour awareness: a risk of neuroblastoma is reported in Weaver syndrome. For Cohen-Gibson syndrome the risk is not established, so keep a low threshold for investigating a mass, persistent pain or unexplained systemic symptoms.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue orthopaedic, behavioural and educational support, and plan transition and supported living.

Monitoring. Growth and pubertal progress every 6 months in childhood. Spine review yearly, and development every 6 to 12 months.

Referral and escalation. Refer to clinical genetics, paediatric endocrinology and orthopaedics. Urgent for an abdominal or other mass, or for severe scoliosis.